Enhanced PI3K/AKT/mTOR responses are associated with resistance to activation-induced cell death and expansion of memory CD4+ T cells in T1D subjects and healthy carriers of the PTPN22 risk variant
Bibliographic record
Abstract
Abstract The genetic variant PTPN22 1858T, encoding Lyp620W, confers increased risk for multiple autoimmune diseases including Type 1 diabetes (T1D). To date, Lyp620W has been associated with increased CD4+memory T cells and enhanced Th1 responses in healthy carriers. However, it is not clear whether this is due to altered lineage commitment and/or survival within the CD4+memory T cell compartment. Here, we determined the mechanism by which Lyp620W alters human CD4+memory T cell homeostasis in PTPN22 1858T carriers and T1D subjects. T1D subjects displayed significantly increased CD4+ memory T cells as compared to healthy individuals irrespective of PTPN22 genotype, which was further increased in homozygous carriers of PTPN22 1858T, suggesting a partial role for this variant. Among healthy 1858T carriers, we found a significant increase in the magnitude of Th1 effector responses, but not enhanced Th1 differentiation. Consistent with increased survival, TCR-induced PI3K/AKT/mTOR pathway responses and BCL-2 expression were augmented in CD4+ memory T cells from healthy 1858T carriers. Importantly, these alterations were associated with increased resistance to TCR-mediated apoptosis in CD4+ memory T cells. Similar changes in PI3K/AKT signaling and T cell survival were observed in the Th1 memory compartment of T1D individuals, and selective inhibition of PI3Kδ reversed the survival phenotypes in memory T cells from both healthy 1858T carriers and T1D subjects. Thus, our combined findings reveal a novel immune ‘signature’ associated with Lyp620W and highlight a clinically-relevant T cell intrinsic mechanism that promotes the survival of potentially pathogenic Th1 effector T cells in T1D.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".